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bioRxiv · 10.1101/2022.12.16.520790

A histone methyltransferase point mutation demonstrates a mechanism for translocation-driven acute leukemias

Kobrossy, L.·Xu, W.·Zhang, C.·Turner, C. E.·Cosgrove, M. S.
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Abstract

Our understanding of acute leukemia pathology is heavily dependent on 11q23 chromosomal translocations involving the mixed lineage leukemia-1 (MLL1) gene, a key player in histone H3 lysine 4 (H3K4) methylation. These translocations result in distinct MLL1-fusion (MLL1F) proteins that are thought to drive leukemogenesis. However, the mechanism behind increased H3K4 trimethylation in MLL1F-leukemic stem cells (MLL1F-LSCs), following loss of catalytic SET domain of MLL1 (known for H3K4 mono- and dimethylation), remains unclear. In our investigation, we introduced a homozygous loss-of-function point mutation in MLL1 within human induced pluripotent stem cells. Remarkably, this mutation mimics the histone methylation, gene expression, and EMT phenotypes of MLL1F-LSCs- without the need for a translocation or functional wild-type MLL1. This observation underscores the essential role of MLL1s enzymatic activity in restraining the cascade of epigenetic changes associated with the gene activating H3K4 trimethylation mark, which we show is catalyzed by mislocalized SETd1a H3K4 trimethyltransferase in the absence of MLL1s enzymatic activity. Challenging existing models, our findings imply that MLL1F-induced leukemias arise from a dominant-negative impact on MLL1s histone methyltransferase activity. We advocate for a therapeutic paradigm shift, targeting SETd1a for precision medicine. This work opens new avenues for addressing the complexities of MLL1-associated leukemias and improving targeted therapies. SummaryEpigenomic and gene expression changes in iPS cells with a mutated MLL1 histone methyltransferase suggest an oncogenic mechanism for MLL1-fusion leukemias.

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Kobrossy, L., Xu, W., Zhang, C., Turner, C. E., Cosgrove, M. S.. 2022-12-19. A histone methyltransferase point mutation demonstrates a mechanism for translocation-driven acute leukemias. https://doi.org/10.1101/2022.12.16.520790

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